Dexmedetomidine-esketamine Combined Nasal Administration and Emergence Delirium

Effect of Dexmedetomidine-esketamine Combined Nasal Administration on Emergence Delirium in Elderly Patients After Surgery: a Randomized, Double-blind, Placebo-controlled Trial

Emergence delirium is common in older patients after surgery and associated with worse perioperative outcomes, including increased postoperative delirium. Nasal administrations of both dexmedetomidine and esketamine are approved for medical purposes. Combination of low-dose dexmedetomidine and esketamine has shown some synergic effects in analgesia and anxiolysis. In a recent randomized trial, combined nasal administration of dexmedetomidine and esketamine was more effective in reducing pre-dental anxiety in pediatric patients. The investigators hypothesize that perioperative nasal administration of dexmedetomidine-esketamine combination can reduce the incidence of emergence delirium in older patients after surgery.

Delirium is a common brain dysfunction syndrome in older patients after major surgery. Delirium that occurs after surgery includes emergence delirium and postoperative delirium. Emergence delirium occurred in 17.5% to 37.0% of patients following general anesthesia. The reported incidence of postoperative delirium ranged from 12.0% to 32.9% in older patients after noncardiac surgery. It is well known that the occurrence of postoperative delirium is associated with adverse outcomes. Recent studies found that emergence delirium is also associated with adverse perioperative outcomes, including increased postoperative delirium, more non-delirium complications, longer hospital stay, and higher healthcare costs.

Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with sedative, anxiolytic, and analgesic effects. Prophylactic administration of dexmedetomidine preoperatively or intraoperatively has also been shown to reduce the incidence of postoperative delirium. Dexmedetomidine via nasal administration is now widely used for pediatric preoperative sedation. Nasal administration of dexmedetomidine is also used in adults. In a retrospective study, postoperative nasal administration of dexmedetomidine (100 μg) to elderly orthopedic surgical patients improved analgesia and reduced symptoms of agitation. A recent study of patients undergoing gynecologic laparoscopic surgery, night-time dexmedetomidine (1.5 µg/kg) administration by nasal drops from preoperative day 1 to postoperative day 5 improved sleep quality and reduced the incidence of postoperative delirium.

Esketamine is a N-methyl-D-aspartic acid receptor antagonist and has been used as an anesthetic and analgesic. Low-dose intravenous infusion of ketamine is recommended for postoperative analgesia. Esketamine is s-enantiomer of ketamine and twice as potent as ketamine in analgesic potency. Nasal administration of esketamine is approved by FDA for intractable depression in adults. A randomized trial showed that nasal application of esketamine was effective in relieving post-thoracic puncture pain in adult patients without significant adverse effects. And postoperative pain is a common risk factor of emergence delirium and postoperative delirium.

This randomized trial is designed to test the hypothesis that combined nasal administration of dexmedetomidine-esketamine combination may reduce the incidence of emergence delirium in older patients after surgery.

Inclusion Criteria:

1. Aged ≥ 65 years;
2. Scheduled for inpatient elective or semi-elective surgery under general anesthesia, with an expected surgical duration of ≤2 hours;
3. Planned to stay in hospital for at least 1 day after surgery.

Exclusion Criteria:

1. Not suitable for intranasal drug administration due to nasal disease (e.g., rhinitis, nasal polyps, or nasal congestion due to any cause);
2. Preoperative schizophrenia, epilepsy, Parkinson's disease, myasthenia gravis, or delirium;
3. Inability to communicate due to coma, severe dementia, or language barrier before surgery;
4. Brain trauma or neurosurgery;
5. Use of sedatives or hypnotics at bedtime during the last month;
6. History of hyperthyroidism or pheochromocytoma;
7. Preoperative left ventricular ejection fraction <30%, or sick sinus node syndrome, severe sinus bradycardia (heart rate <50 beats per minute), or atrioventricular block of degree II or higher without pacemaker, or systolic blood pressure <90 mmHg before enrollment;
8. Severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (receiving dialysis before surgery), or American Society of Anesthesiologists classification ≥ IV;
9. Planned admission to the intensive care unit after surgery;
10. Allergic to dexmedetomidine and/or esketamine, or any other conditions that are considered unsuitable for study participation.